Innovating anti-tuberculosis drug susceptibility testing with a novel and rapid non-culture based phenotypic test using MPT64 biomarker

Active Project Grant Awarded Last action

Award ID
R01AI176409
Recipient
Awarding agency
Obligated
$4,897,238

Award facts

Assistance listing
93.855 Allergy and Infectious Diseases Research
Completion date 71% complete
Place of performance
San Francisco, CA 94110, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
30 lines drug-resistant tuberculosis (TB) threatens our goal of ending the global TB epidemic by 2035. Early diagnosis of drug-resistant TB for timely initiation of appropriate treatment remains a challenge. Phenotypic drug susceptibility testing (DST) requires mycobacterium tuberculosis (MTB) culture and takes 8-12 weeks. Molecular-based methods are rapid but require previously identified and validated resistance-conferring mutations. Unfortunately, mutations are not completely known for key drugs included in newer all-oral regimens. Our long-term goal is to develop a non-culture-based method for phenotypic DST that provides results in 48-72 hours from sputum collection and that can be used directly on sputum. Our innovative approach is based on MPT64, a protein secreted only during active growth that is highly specific for MTB. We demonstrated that MPT64 secretion in MTB cultures decreases significantly within 48-72 hours of anti-TB drug exposure for drug-susceptible but not drug-resistant MTB isolates. We have previously measured MPT64 directly in sputum samples with a limit of detection comparable with xpert MTB/RIF ultra (cepheid, sunnyvale, CA, USA). In this study we will validate culture MPT64 DST chemiluminescence-enzyme immunoassay (clea) for isoniazid (INH), rifampin (RIF), fluoroquinolones (FQS), bedaquiline (BDQ), linezolid (LZD), and delamanid (DLM). Our proposed approach will provide results within 72 hours of the time the culture is identified as MTB, compared to the 2-3 weeks required to obtain results from conventional DST (aim 1). We will use the principles of culture MPT64 DST to develop a sputum MPT64 DST cleia, which will provide results in 48-72 hours from the time of sputum collection. We will identify protocols for sputum liquefaction, antibiotic exposure times, and cleia that result in the lowest limit of detection (LOD) for resistant MTB cells (aim 2). We will prospectively evaluate sputum MPT64 DST in 860 patients with TB in the philippines and in the country of georgia (aim 3). We hypothesize that both culture MPT64 DST and sputum MPT64 DST will meet or exceed minimum sensitivity (>95%) and specificity (>98%), which are the who high priority target product profiles for rapid DST. The innovative MPT64 DST assays will transform TB management by enabling early initiation of effective treatment based on rapid drug susceptibility data, thus improving patient outcomes and curtailing the spread of drug resistant TB that is critical if TB is to be eliminated by 2035.

Transactions

Action Obligated Date
Amendment $136,279
Amendment $153,127
Amendment $343,420
Amendment $343,420
Amendment $632,826
Amendment $633,020
Amendment $633,020
Amendment $8,247
Amendment $8,247
Amendment $668,544
Amendment $668,544
Original award $668,544
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Subawards

Subrecipient Amount Awarded
National Center For Lung Health JSC Responsibilities: Day to day shall be managed on a day-to-day basis by Nestani Tukvadze, MD/Maia Kipiani, MD. (study site PI) or their delegate. It is envisaged… $306,270
Japan Anti-Tuberculosis Association Responsibilities: Day to day shall be managed on a day-to-day basis by Satoshi Mitarai (study site PI) or their delegate. It is envisaged that said tasks will… $374,069
University Of The Philippines Manila Our long-term goal is to develop a non-culture-based method for phenotypic DST that provides results in 48-72 hours from sputum collection and that can be… $290,553

Quick answers

Who received award R01AI176409?

R01AI176409 was awarded to The Regents Of The University Of California. San Francisco by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on April 4, 2023.

How much is award R01AI176409 worth?

$4,897,238 has been obligated on R01AI176409.

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